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IRF6 is critical mediator of alternative macrophage activation
Author(s) -
Tseng Alexander Mike,
Cheng ChangAn,
Wang Haiqing,
Lin YuLieh,
Zhou Beiyan,
Brehm Tyler
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb652
Subject(s) - microbiology and biotechnology , irf5 , interferon regulatory factors , chromatin immunoprecipitation , macrophage polarization , transcription factor , biology , small hairpin rna , macrophage , innate immune system , immune system , immunology , gene expression , cell culture , gene knockdown , promoter , biochemistry , genetics , gene , in vitro
Macrophages display a spectrum of activated phenotypes in response to microenvironmental signals. Pro‐inflammatory and anti‐inflammatory macrophages have important roles in promoting or resolving disease states and also regulate homeostatic conditions of the tissues they reside in, as is the case with adipose tissue macrophages (ATMs). Indeed, under obese stress ATMs expand in number and undergo predominantly pro‐inflammatory activation which propagates dysregulated metabolic and immunologic adipose tissue homeostasis. In this study, we report a new regulator, IRF6, in controlling macrophage alternative activation (M2). IRF6 is a member of the interferon regulatory transcription factors (IRFs) which share a high degree of conservation in their DNA binding domain but less similarity within their protein interaction domain. Knowledge of IRF6 is currently limited to its role in mediating epithelial cell differentiation and the epithelial innate immune response to pathogen challenge. We observed that expression of IRF6 was dramatically suppressed in M2 macrophages. Using both gain and loss of function strategies, we further confirmed that IRF6 specific shRNA enhanced M2 activation as evidenced by elevated levels of activation‐related cell surface markers CD69 and CD86 and the expression of M2‐related genes including IRF4, PPARγ, Arginase1, and IL10. Conversely, IRF6 overexpression dramatically attenuated M2 activation. Furthermore, chromatin immunoprecipitation revealed IRF6 regulates anti‐inflammatory macrophage activation by repressing the expression of PPARy, a critical mediator of macrophage polarization, through binding two IRF recognition sites located upstream of the PPARγ coding region. Our investigation also indicated IRF6 expression is significantly increased in obese ATMS, suggesting that a dysregulated IRF6/PPARγ regulatory axis suppresses anti‐inflammatory ATM responses and ultimately contributes to dysregulated metabolic and immunologic homeostasis. Support or Funding Information This work was supported by the Texas A&M Graduate Merit Fellowship (to A. Tseng), American Diabetes Association (1‐13‐JF‐59 to B. Zhou) and National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK 1R01DK098662 to B. Zhou).